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ERBB3 is required for metastasis formation of melanoma cells.

Tiwary S, Preziosi M, Rothberg PG, Zeitouni N, Corson N, Xu L - Oncogenesis (2014)

Bottom Line: Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro.These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs.In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

ABSTRACT
Melanoma is curable when it is at an early phase but is lethal once it becomes metastatic. The recent development of BRAF(V600E) inhibitors (BIs) showed great promise in treating metastatic melanoma, but resistance developed quickly in the treated patients, and these inhibitors are not effective on melanomas that express wild-type BRAF. Alternative therapeutic strategies for metastatic melanoma are urgently needed. Here we report that ERBB3, a member of the epidermal growth factor receptor family, is required for the formation of lung metastasis from both the BI-sensitive melanoma cell line, MA-2, and the BI-resistant melanoma cell line, 451Lu-R. Further analyses revealed that ERBB3 does not affect the initial seeding of melanoma cells in lung but is required for their further development into overt metastases, indicating that ERBB3 might be essential for the survival of melanoma cells after they reach the lung. Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro. These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs. In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

No MeSH data available.


Related in: MedlinePlus

The pan-ERBB inhibitor, canertinib, inhibits metastasis formation of BI-resistant melanoma cells. (a, b) Canertinib treatment led to a reduction in metastases from 451Lu-R cells (a) and MeWo cells (b). Left: human-specific vimentin staining of the mouse lung sections treated with vehicle or canertinib. Metastases are in red and indicated by black arrows. Right: the number of lung metastases from canertinib- or vehicle-treated mice. *P<0.05; **P<0.01. (c) Survival probability of 451Lu-R metastases-bearing mice, treated with canertinib or vehicle.
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fig6: The pan-ERBB inhibitor, canertinib, inhibits metastasis formation of BI-resistant melanoma cells. (a, b) Canertinib treatment led to a reduction in metastases from 451Lu-R cells (a) and MeWo cells (b). Left: human-specific vimentin staining of the mouse lung sections treated with vehicle or canertinib. Metastases are in red and indicated by black arrows. Right: the number of lung metastases from canertinib- or vehicle-treated mice. *P<0.05; **P<0.01. (c) Survival probability of 451Lu-R metastases-bearing mice, treated with canertinib or vehicle.

Mentions: Our above findings imply that ERBB3 might be a therapeutic target for melanoma metastasis, particularly those resistant to BIs. ERBB3 does not have a functional kinase domain at its C-terminus, so its signaling relies on dimerization with other ERBB members. To maximize the effects on ERBB3 inhibition, we obtained the irreversible pan-ERBB inhibitor, canertinib,35, 36 for our study. Two BI-resistant melanoma cell lines, 451Lu-R and MeWo, were injected intravenously into NSG mice. Once the metastases were established, the injected mice were treated daily with canertinib, or vehicle, for a few days and then left off drug for an additional period of time before being euthanized for analyses (see Materials and methods). Their lungs were harvested, sectioned and stained with the anti-vimentin antibody to score metastases. Canertinib treatment led to a significant reduction in metastasis formation from both 451Lu-R and MeWo cells (Figures 6a and b). We also assessed the potential of canertinib on prolonging the survival of metastasis-bearing mice. A small group of mice carrying 451Lu-R metastases were kept for 64 days after the start of treatment. The vehicle-treated mice (n=3) died on day 46, 49 and 64, whereas two of the three canertinib-treated mice were still alive on day 64 and one died on day 58. Although the sample size in each group is too small to allow a reliable statistical calculation, canertinib-treated mice appeared to have prolonged survival relative to the vehicle-treated mice (Figure 6c), suggesting that pan-ERBB inhibitors may have therapeutic effects on treating BI-resistant metastatic melanoma.


ERBB3 is required for metastasis formation of melanoma cells.

Tiwary S, Preziosi M, Rothberg PG, Zeitouni N, Corson N, Xu L - Oncogenesis (2014)

The pan-ERBB inhibitor, canertinib, inhibits metastasis formation of BI-resistant melanoma cells. (a, b) Canertinib treatment led to a reduction in metastases from 451Lu-R cells (a) and MeWo cells (b). Left: human-specific vimentin staining of the mouse lung sections treated with vehicle or canertinib. Metastases are in red and indicated by black arrows. Right: the number of lung metastases from canertinib- or vehicle-treated mice. *P<0.05; **P<0.01. (c) Survival probability of 451Lu-R metastases-bearing mice, treated with canertinib or vehicle.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: The pan-ERBB inhibitor, canertinib, inhibits metastasis formation of BI-resistant melanoma cells. (a, b) Canertinib treatment led to a reduction in metastases from 451Lu-R cells (a) and MeWo cells (b). Left: human-specific vimentin staining of the mouse lung sections treated with vehicle or canertinib. Metastases are in red and indicated by black arrows. Right: the number of lung metastases from canertinib- or vehicle-treated mice. *P<0.05; **P<0.01. (c) Survival probability of 451Lu-R metastases-bearing mice, treated with canertinib or vehicle.
Mentions: Our above findings imply that ERBB3 might be a therapeutic target for melanoma metastasis, particularly those resistant to BIs. ERBB3 does not have a functional kinase domain at its C-terminus, so its signaling relies on dimerization with other ERBB members. To maximize the effects on ERBB3 inhibition, we obtained the irreversible pan-ERBB inhibitor, canertinib,35, 36 for our study. Two BI-resistant melanoma cell lines, 451Lu-R and MeWo, were injected intravenously into NSG mice. Once the metastases were established, the injected mice were treated daily with canertinib, or vehicle, for a few days and then left off drug for an additional period of time before being euthanized for analyses (see Materials and methods). Their lungs were harvested, sectioned and stained with the anti-vimentin antibody to score metastases. Canertinib treatment led to a significant reduction in metastasis formation from both 451Lu-R and MeWo cells (Figures 6a and b). We also assessed the potential of canertinib on prolonging the survival of metastasis-bearing mice. A small group of mice carrying 451Lu-R metastases were kept for 64 days after the start of treatment. The vehicle-treated mice (n=3) died on day 46, 49 and 64, whereas two of the three canertinib-treated mice were still alive on day 64 and one died on day 58. Although the sample size in each group is too small to allow a reliable statistical calculation, canertinib-treated mice appeared to have prolonged survival relative to the vehicle-treated mice (Figure 6c), suggesting that pan-ERBB inhibitors may have therapeutic effects on treating BI-resistant metastatic melanoma.

Bottom Line: Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro.These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs.In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

ABSTRACT
Melanoma is curable when it is at an early phase but is lethal once it becomes metastatic. The recent development of BRAF(V600E) inhibitors (BIs) showed great promise in treating metastatic melanoma, but resistance developed quickly in the treated patients, and these inhibitors are not effective on melanomas that express wild-type BRAF. Alternative therapeutic strategies for metastatic melanoma are urgently needed. Here we report that ERBB3, a member of the epidermal growth factor receptor family, is required for the formation of lung metastasis from both the BI-sensitive melanoma cell line, MA-2, and the BI-resistant melanoma cell line, 451Lu-R. Further analyses revealed that ERBB3 does not affect the initial seeding of melanoma cells in lung but is required for their further development into overt metastases, indicating that ERBB3 might be essential for the survival of melanoma cells after they reach the lung. Consistent with this, the ERBB3 ligand, NRG1, is highly expressed in mouse lungs and induces ERBB3-depdnent phosphorylation of AKT in both MA-2 and 451Lu-R cells in vitro. These findings suggest that ERBB3 may serve as a target for treating metastatic melanomas that are resistant to BIs. In support of this, administration of the pan-ERBB inhibitor, canertinib, significantly suppresses the metastasis formation of BI-resistant melanoma cell lines.

No MeSH data available.


Related in: MedlinePlus